Torasemide is a known compound which has been approved by the U.S. Food and Drug Administration for use as a diuretic.
Torasemide (1-isopropyl-3-(4-m-toluidino-3pyridyl)-sulphonyl)-urea) is a compound with interesting pharmacological properties which is described in Example 71 of U.S. Pat. No. Re 30,633 as 3-isopropylcarbarmylsulfonamido-4-(3'-methyl)-phenylaminopyridine. In particular, this compound belongs to the class of loop diuretics as it blocks the sodium-potassium-2 chloride transport mechanism in the ascending limb of the loop of Henle. In contrast to other standard loop diuretics, however, it shows a less intense initial diuresis and a sustained duration of action.
In the preparation of torasemide, a purification is normally included in which the compound in question is dissolved in an aqueous or aqueous alcoholic solution of sodium hydrogen carbonate and, after filtering off from impurities, the torasemide is again precipitated out with an inorganic acid. In the case of this process, the product is obtained in the form of white crystals with a melting point of 163.degree.-164.degree. C. U.S. Pat. No. Re 30,633 does not mention any particular crystalline form of torasemide.
From Acta Cryst. 1978, pp. 2659-2662 and Acta Cryst., 1978, pp. 130.4-1310, it is known that torasemide can occur in two modifications each having a different X-ray crystallograph. Both modifications are simultaneously present when a solution of torasemide in petroleum ether/ethanol is slowly evaporated. The crystals, which are characterized not only as prisms with a melting point of 159-161.5.degree. C. but also as leaflets with a melting point of 157.5-160.degree. C., are, however, only described in these literature references with regard to their X-ray crystallographic properties. The modification with the melting point of 159-161.5.degree. C., which is hereinafter referred to as modification I, crystallizes monoclinically in the space group P2.sub.1 /c and has a true density of about 1.36, and the modification with the melting point of 157.5-160.degree. C., which is hereinafter referred to as modification II, crystallizes monoclinically in the space group P2/n and has a true density of 1.285.
The modification obtained in the case of the preparation and normal purification by precipitating the torasemide from an aqueous solution is modification II which usually also results in the case of recrystallisations from other solvents. Since this form, in the case of storage of the pure active material, does not change and, in the case of all purification experiments, forms the predominant form, it was assumed that this modification II was stable.
U.S. Reissue Pat. Nos. 34,672 and 34,580 are based on the discovery that torasemide of modification II, when it is present in very finely divided form in pharmaceutical tablets, rearranges more or less quickly into modification I, whereby the crystal size and speed of dissolving of the active material upon introducing the tablets into water can be significantly changed. Since, as was known, the speed of dissolving represents one of the important characteristics of a pharmaceutical form of administration and thus, in order to be able to dose reproducibly, must not differ from one tablet to another, the problem existed of finding a form of administration of torasemide which does not change its speed of dissolving during storage. Since the uncontrollable change of the speed of dissolving depends upon the rearrangement of modification II into modification I of the torasemide, it was obvious ab initio to use modification I. From investigations it was found that modification I is stable in tablets and did not rearrange again back into modification II.
The applicant has recently discovered that a third form of torasemide exists, and has labelled this third form as modification III. Modification III is stable, and has significantly greater solubility than modification I above pH 3 and especially at a pH of approximately 7.4. Modification III is especially suitable for use as a diuretic where a rapid onset of diuretic effect is desired, or as a way to avoid IV therapy, since oral administration could be used.